A safe and effective therapeutic for treatment of osteoarthritis (OA) represents a major unmet medical need. OA is the leading cause of disability in the US and pain is a predominant clinical feature. However, chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with potentially life-threatening gastrointestinal bleeding and calculations estimate that about 100,000 patients are hospitalized annually for NSAID related GI complications and about 16,500 NSAID-related deaths occur among arthritis patients in the US each year, leading to $2 billion in health care costs. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets a key molecule involved in nociceptive signaling from the joint. We propose to develop a novel, first-in-class therapeutic small molecule compound which is a functional antagonist of TRPA1 (Transient Receptor Potential, Subfamily A, member 1) for the treatment of OA pain. TRPA1-receptor/channels serve a highly specific function on sensory nerve fiber endings in the joint that detect and transmit the sensations of pain and hyperalgesia in response to inflammation and nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors in the joint, an antagonist of TRPA1 will function as a peripherally acting analgesic. Our innovative approach is based on development of novel therapeutic agent that will block nociceptive signals at the first stage of neural processing and does not involve CNS action. Algomedix employs a rational pharmacology approach and has already made substantial progress in the identification of novel, small molecule chemical antagonists of TRPA1 The long-term goal of this project is to identify orally available antagonists of TRPA1 that will block the excitation of the nociceptive afferent fibers present in the joint that are activated in OA. This approach is based upon genetic and in vivo pharmacologic evidence that modulation of TRPA1 activity will have therapeutic value. The aims are: AIM 1 will be to synthesize a group of 75 novel, structural analogs based upon newly discovered TRPA1 ligands using a novel scaffold. Synthetic medicinal chemistry and structure guided drug design efforts will be used to enhance lead potency and to further define structure-activity relationships (SAR). AIM 2 will be to define the potency and pharmacological of novel compounds on human and rat TRPA1. In AIM 3, the pharmacological selectivity for novel antagonists will be defined among members of the TRP superfamily using a panel of related TRP channels, including TRPV1, TRPV3, TRPM8 and several TRPC members. AIM 4 will pharmacologically characterize the activity of the new drug using cultured dorsal root ganglion neurons, which are the primary target cell for TRPA1, and AIM 5 will conduct in vitro ADME profiling for the top-ranked active compounds and determine pharmacokinetics using oral dosing. The final Phase 1 milestone is to deliver an advanced lead molecule and backup compounds that have all properties necessary for nomination to a full development program in Phase 2. The anticipated Phase 2 program will consist of animal efficacy testing in multiple OA models and conducting pharmacokinetic studies in multiple animal species using oral dosing to enable the filing of an IND.